In deriving the RfD, EPA relied on the initial published models and a series of memoranda from DOD describing the continued updating of the suite of PBPK models (Clewell 2001a,b; Merrill 2000; Merrill 2001a,b). The final PBPK models were published shortly after the EPA review (Clewell et al. 2003a,b; Merrill et al. 2003) and reflected comments received by EPA’s peer review (EPA 2002c) and journal peer reviewers. The models have similar base structures and sources for model parameter values and additional features where necessary to address specific life stages, such as growth and development and additional compartments associated with pregnancy and lactation in the rat.

The first PBPK model of Fisher et al. (2000) was developed to describe the disposition of perchlorate in the adult male rat; it was based on rather sparse kinetic data that were available in the late 1990s. Tissues that were specifically included in the initial framework included lungs, kidneys, thyroid, and gastrointestinal (GI) tract; the remaining tissues were lumped into either poorly perfused or richly perfused compartments (Figure E-1). Each of those compartments consisted of mass-balance equations describing the rates of transfer of perchlorate into and out of each tissue on the basis of their known volumes, blood perfusion rates, partition coefficients, the presence (or absence) of any transport processes (such as that of the NIS in thyroid and GI tract), or the clearance of perchlorate into urine. Only sparse data on perchlorate after intravenous (IV) administration were available for model development. On the basis of the the preliminary analysis, it was observed that perchlorate clearance into urine after IV dosing at 0.01-3 mg/kg followed linear, first-order kinetics, whereas substantial nonlinearities were observed in systemic (serum and tissue) kinetics. Thus, the preliminary model was used as an initial framework for identifying critical data gaps for later model development and definitions of relevant internal-dose surrogates (as opposed to administered doses or external exposures) that could be used to enhance human health risk assessments that were based on toxicity studies in rats.

Clewell et al. (2001) later proposed a suite of initial PBPK models that incorporated important steps in the mode of action of perchlorate (NIS iodide uptake inhibition) and key life stages for perchlorate toxicity (fetus and neonate) in addition to the adult male. To accomplish that, initial PBPK models were developed for perchlorate and iodide with interactions between them occurring at the NIS. The purpose of the preliminary PBPK models was to lay the groundwork for extrapolating the internal doses of perchlorate (such as blood concentrations and interactions with iodide in thyroid NIS) from rats to humans as a function of life stage (fetus, neonate,



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